The purpose of these studies is to continue to assess the role of free radicals and the toxicity of MDMA in transgenic and nontransgenic mice. Administration of 3,4-methylenedioxymethamphetamine (4 x 20 mg/kg) to non-transgenic CD-1 mice caused marked depletion in dopamine, 3,4- dihydroxyphenylacetic acid and 5-hydroxytryptamine in the caudate- putamen. There were no significant changes in serotonergic markers in the hippocampus and frontal cortex. Homozygous and heterozygous copper/zinc superoxide dismutase transgenic mice show partial protection against the toxic effects of 3,4- methylenedioxymethamphetamine on striatal dopaminergic markers. In addition, 3,4-methylenedioxymethamphetamine injections caused marked decreases in copper/zinc superoxide dismutase activity in the frontal cortex, caudate-putamenand hippocampus of wild-type mice. Moreover, there were concomitant 3,4-methylenedioxymethamphetamine-induced decreases in catalase activity in the caudate-putamen and hippocampus, decreases in glutathione peroxidase activity in the frontal cortex as well as increases in lipid peroxidation in the frontal cortex, caudate- putamen, and hippocampus of wild-type mice. In contrast, administration of 3,4-methylenedioxymethamphetamine to homozygous superoxide dismutase transgenic mice caused no significant changes in antioxidant enzyme activities nor in lipid peroxidation. These results provide further substantiation of a role for oxygen-based radicals in 3,4- methylenedioxymetham- phetamine-induced neurotoxicity. The present data also suggest that free radicals generated during 3,4- methylenedioxymeth- amphetamine administration may perturb antioxidant enzymes. Consequently, there might be further overproduction of free radicals with associated peroxidative damage to cell membranes and associated terminal degeneration. - MDMA, Transgenic Mice, Superoxide Dismutase, Dopamine Metabolism, Catalase, Glutathione Peroxidase